.DELTA..sup.1 -Tetrahydrocannabinol (THC) (Formula I) is the major psychoactive constituent of marijuana (Hollister, L.E. Science, 172:21-29, 1971; Isbell, H., Gorodetsky, C. W., Jasinski, D., Claussen, V., von Spulak, F. and Korte, F. Psychopharmacologia, 11:184-188, 1967; Mechoulam, R., Science, 168:1159-1166, 1970). The initial metabolites of THC are monohydroxy derivatives active as mood-altering agents. It is believed that these monohydroxy derivatives of THC contribute to the overall effects of the drug, but their presence is not required for the psychotropic action of cannabis (Harvey, D. J. and Paton, W. D. M. Rev. Biochem. Toxic. 6:250, 1984).
Metabolism of the monohydroxy THC derivatives involves a series of oxidative transformations that ultimately leads to a group of carboxyl-containing derivatives of the parent substance. These acidic metabolites were thought to display none of the biological activities of their precursors and have been generally regarded as inactive metabolic end-products. The most abundant member of this group is the cannabinoid .DELTA..sup.1 -THC-7-oic-acid (Formula II). When tested in humans as well as in the rhesus monkey, this cannabinoid did not show the behavioral activity or the cardiovascular effects characteristic of the parent substance, THC. (Perez-Reyes, M. In: Pharmacokinetics and Pharmacodynamics of Psychoactive Drugs, Barnett, G. and Chiang, N. (eds), Biomedical Press, 1985, pages 287-310; Mechoulam, R. and Edery, M. In: Marijuana, Mechoulam, R. (ed.), Academic Press, New York, 1973). Thus, little attention has been given to the possible pharmacodynamic properties of this metabolite or any of the other acid metabolites of THC. ##STR1##
It has long been known that THC possesses potent analgesic and anti-inflammatory properties. However, the biochemical bases for these effects was not well understood. Although it has been suggested that the THC-induced elevation of plasma corticosteroids was responsible, the experimental support for this hyopthesis is inconclusive (Sophia, R. D., Nalepa, S. D., Harakal, J. J. and Vassar, H. B., J. Pharma. Exper. Ther. 186:646-655, and 1973). It has also been shown, in a variety of models that .DELTA..sup.1 -THC-7-oic-acid can be a potent inhibitor of the prostaglandin synthetase system (Burstein, S., Hunter, S. A., Lathan, V. and Renzulli, L., Biochem. Pharmac. 35:2553-2558, 1986).
The .DELTA..sup.1 -THC-7-oic-acid metabolite has also been shown to antagonize the in vitro action of the parent substance (Burstein, S., Hunter, S. A., Latham, V. and Renzulli, L. Biochem. Pharmac. 35: 2553-2558, 1986). The system in which this observation was made involved exposing cells in culture to cannabinoids and measuring the change brought about in the metabolism of arachidonic acid (Burstein, S., Hunter, S. A. and Ozman, K. Molec. Pharmac. 23:121, 1983; Burstein, S. and Hunter, S. A. J. Clin. Pharmac. 21:2405, 1981; Burstein, S. Hunter, S. A., Sedor, C. and Shulman, S. Biochem. Pharmac. 31:2361, 1982). The addition of the metabolite to the culture medium prior to THC exposure resulted in a dramatic lowering of the stimulatory effect of THC on prostaglandin synthesis. A kinetic and chromatographic analysis of the metabolic products in the media suggested that cycloxygenase may be the site of inhibition by the .DELTA..sup.1 -THC-7-oic acid (Burstein, S. et al., Biochem. Pharmac. 35:2553-2558, 1986).